Parkinson's disease is a widespread and debilitating aging-related neurodegenerative disorder. The incidence for Parkinson's disease is increasing in parallel with life expectancy. There is no cure or means of slowing the progression of this disease. Although current symptomatic therapies are initially effective, they are short-lived because disease progression cannot be arrested. Recent preclinical and epidemiological studies have implicated L-type Ca2+ channels with a CaV1.3 pore-forming subunit in disease pathogenesis. Although a clinical trial with a dihydropyridine (DHP) antagonist of these channels is underway, this trial could fail because off-target effects limit dosing. Thus, the development o a potent and selective CaV1.3 channel antagonist with good pharmacokinetics and low toxicity is an unmet need for the Parkinson's disease community. To meet this need, a high-throughput screening (HTS) effort was undertaken and two small molecules with low CaV1.3 selectivity were identified that had excellent pharmacological properties. A third scaffold has been identified using a computational approach informed by our HTS screen. Structure modification of one of the molecules led to an 833-fold increase in CaV1.3 selectivity (to 1000-fold). This proposal requests support to take the next steps toward developing these scaffolds into clinically useful drugs. Three specific aims are proposed: Specific Aim 1: To determine the ADMET liabilities of identified CaV1.3 channel antagonists; Specific Aim 2: To improve the potency, selectivity, stability, and brain bioavailability of identified CaV1.3 channel antagonists through medicinal chemistry; and Specific Aim 3: To determine the efficacy of the optimized lead compounds in models of Parkinson's disease. These studies will take full advantage of our early work with these scaffolds by our group and our expertise in assays of drug action in models of Parkinson's disease, complementing the drug development expertise of the NIH contractors. Achieving these aims will provide the first highly selective CaV1.3 channel antagonist suitable for human clinical trials in Parkinson's disease. Such a drug would have the potential to slow or stop the progression of Parkinson's disease, broadening the therapeutic window for symptomatic therapy. PUBLIC HEALTH RELEVANCE: Parkinson's disease is a major health problem in the U.S. Preclinical and epidemiological studies suggest that antagonizing a special class of calcium channel could slow or stop the progression of the disease. The studies proposed here are to develop a new selective antagonist of these channels for clinical use.